A previous 15N NMR relaxation study indicated that the rotational dynamics of calmodulin can be described by nearly isotropic reorientation of each of its globular domains on time scales of ~7.3 ns for the N-terminal domain, and 6.5 ns for its smaller C-terminal domain (Barbato, G., Ikura, M., Kay, L. E., Pastor, R. W., Bax, A. (1992) Biochemistry 31, 5269-5278). A small degree of residual anisotropy was noted in that study, however. Study of the field dependence of the 15N T1 relaxation times have now been carried out at 36, 51 and 61 MHz, at three different temperatures. These data indicate that the reorientation is not compatible with an isotropic tumbling, but requires a model in which anisotropic overall tumbling is combined with large amplitude domain motions. Accurate characterization of the amplitude and the time scale of the domain motion requires that the 15N T1 also be studied at 75 MHz. In addition, it is essential to recognize contributions made by slow conformational averaging to the T2 relaxation times. In the case of anisotropic tumbling, the only reliable way to distinguish correlation time effects from conformational exchange is to measure T2 at different fields. The conformational averaging contribution increases with the square of the field strength and comparison of measurements at 76 MHz with those at lower fields provides a sensitive monitor for detecting such effects.